FBXL5 is a substrate recognition component of the SCF (SKP1-cullin-F-box) E3 ubiquitin ligase complex that serves as a critical regulator of cellular iron homeostasis 1. The protein functions as an iron and oxygen sensor through two distinct metal-binding domains: an N-terminal hemerythrin-like domain containing a diiron center and a C-terminal domain harboring a redox-sensitive [2Fe-2S] cluster 2. Under iron-replete and normoxic conditions, FBXL5 promotes the ubiquitination and proteasomal degradation of iron regulatory protein 2 (IRP2), the master regulator of cellular iron metabolism 12. The [2Fe-2S] cluster must be maintained in its oxidized state by ambient oxygen to enable IRP2 binding and subsequent degradation, explaining hypoxia-induced IRP2 stabilization 2. Conversely, under iron deficiency, the N-terminal domain becomes destabilized, leading to FBXL5's own degradation 1. Beyond iron homeostasis, FBXL5 regulates other cellular processes including ferroptosis sensitivity through the G3BP1-FBXL5-IRP2 axis 3, lipid metabolism in alcoholic fatty liver disease via TFEB degradation 4, and has been identified as a potential diagnostic marker for postmenopausal osteoporosis 5.